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The bleeding disorder hemophilia A (HemA) requires systemic functional factor VIII protein infusions on prophylactic schedules. Recently, chemically modified mRNAs have emerged as promising protein replacement therapies to reduce repeated infusions and improve safety profiles. However, the influence of base modifications on mRNA translation kinetics to specific cell types remains unexplored. In this study, towards developing mRNA therapeutics for haemophilia A, we synthesized chemically modified mRNAs with commercially available base modifications of adenine, guanine, uridine, and cytidine, and evaluated in vitro transcription yield and translation kinetics in hepatic cell lines using reporter eGFP mRNA. Our findings demonstrated that mRNA with N 1 -methyl pseudouridine (m 1 Ψ) showed a 5-12-fold increase in translation efficiency in both hepatic and endothelial cell lines. As a proof of concept for developing mRNA therapy for HemA, where FVIII is deficient, we developed a m 1 Ψ modified functional FVIII mRNA with our liver-targeting lipid nanoparticle (Gal-LNP) system. We evaluated its delivery efficiencies in both hepatic cell lines and the HemA mouse model. The m 1 Ψ-FVIII mRNA showed high therapeutic efficacy up to 15 days in vivo Ψ base modifications on mRNAs could improve therapeutic efficacy in liver- and endothelial-based therapeutics. Optimized mRNA synthesis for superior expression kinetics in hepatic cells and its delivery with liver-targeted nanoparticles may emerge as protein replacement therapies for monogenic liver disorders.1 Ψ base modifications on mRNAs could improve therapeutic efficacy in liver- and endothelial-based therapeutics. Optimized mRNA synthesis for superior expression kinetics in hepatic cells and its delivery with liver-targeted nanoparticles may emerge as protein replacement therapies for monogenic liver disorders.

A surface-modified mesoporous silica nanoparticle containing dimercaprol monomers was created utilizing the sol-gel condensation process, using tetraethyl orthosilicate (TEOS) as the silica source and poloxamer as the structure directing agent. To accomplish this synthesis, 3-glycidoxypropyl triethoxysilane (GPTS, 20 mol%) was incorporated into the silica walls during the sol-gel condensation process, along with TEOS. Furthermore, dimercaprol (DM) monomers were incorporated onto silica surfaces by a ring-opening reaction between GPTS epoxy groups, and dimercaprol hydroxyl groups. The prepared dimercaprol-modified silica adsorbent (MSN-DT NPs) material has been studied using a variety of instruments, including XRD, FT-IR, N 2 adsorption-desorption, scanning electron microscopy (SEM), transmission electron microscopy (TEM), thermogravimetric (TG) analysis, and zeta potential analysis. The MSN-DT NPs material selectively adsorbs mercury ions, with a high adsorption amount of 125 mg/g and a removal capability of roughly ~ 90% from the original metal ion mixture comprising other competing metals such as Pb 2+ , Ni 2+ , Fe 2+ , and Zn 2+ . The MSN-DT NPs adsorbent shows recyclable qualities for up to five cycles when treated with an acidic aqueous solution (0.1 M HCl). As a result, the MSN-DT NPs adsorbent may be regenerated and reused up to five times without losing its adsorption effectiveness. The experimental findings showed that the MSN-DT NPs adsorbent may be employed to selectively remove hazardous Hg 2+ ions from an aqueous solution., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Lipid nanoparticle (LNP)-encapsulated mRNA has been used for in vivo production of several secreted protein classes, such as IgG, and has enabled the development of personalized vaccines in oncology. Establishing the feasibility of delivering complex multispecific modalities that require higher-order structures important for their function could help expand the use of mRNA/LNP biologic formulations. Here, we evaluated whether in vivo administration of mRNA/LNP formulations of SIRPα-Fc-CD40L and TIGIT-Fc-LIGHT could achieve oligomerization and extend exposure, on-target activity, and antitumor responses comparable with that of the corresponding recombinant fusion proteins. Intravenous infusion of the formulated LNP-encapsulated mRNAs led to rapid and sustained production of functional hexameric proteins in vivo, which increased the overall exposure relative to the recombinant protein controls by ∼28 to 140 fold over 96 hours. High concentrations of the mRNA-encoded proteins were also observed in secondary lymphoid organs and within implanted tumors, with protein concentrations in tumors up to 134-fold greater than with the recombinant protein controls 24 hours after treatment. In addition, SIRPα-Fc-CD40L and TIGIT-Fc-LIGHT mRNAs induced a greater increase in antigen-specific CD8+ T cells in the tumors. These mRNA/LNP formulations were well tolerated and led to a rapid increase in serum and intratumoral IL2, delayed tumor growth, extended survival, and outperformed the activities of benchmark mAb controls. Furthermore, the mRNA/LNPs demonstrated improved efficacy in combination with anti-PD-L1 relative to the recombinant fusion proteins. These data support the delivery of complex oligomeric biologics as mRNA/LNP formulations, where high therapeutic expression and exposure could translate into improved patient outcomes., Significance: Lipid nanoparticle-encapsulated mRNA can efficiently encode complex fusion proteins encompassing immune checkpoint blockers and costimulators that functionally oligomerize in vivo with extended pharmacokinetics and durable exposure to induce potent antitumor immunity., (©2024 The Authors; Published by the American Association for Cancer Research.)

In the present study, ZnO nanoparticles have been synthesized using an aqueous extract of shilajit. The nanoparticles were characterized using different techniques such as UV (ultraviolet-visible spectrophotometer), FTIR (Fourier transform infrared), XRD (X-ray diffraction), particle size analysis, SEM (scanning electron microscope) and EDAX (Energy-dispersive X-ray) analysis. The UV absorption peak at 422.40 nm was observed for ZnO nanoparticles. SEM analysis showed the shape of nanoparticles to be spherical, FTIR spectrum confirmed the presence of zinc atoms, particle size analysis showed the nanoparticle size, EDAX confirmed the purity of ZnO nanoparticles whereas XRD pattern similar to that of JCPDS card for ZnO confirmed the presence of pure ZnO nanoparticles. The in vitro anticancer activity of ZnO nanoparticles against the HeLa cell line showed the IC 50 value of 38.60 μg/mL compared to reference standard cisplatin. This finding confirms that ZnO nanoparticles from shilajit extract have potent cytotoxic effect on human cervical cancer cell lines., (© 2024. The Author(s).)